Gall, U.S. Pat. No. 4,001,262 describes and claims a process for reacting a 1-hydrogen-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepine with a reagent ##STR2## where X.sup..crclbar. is the anion of a monovalent inorganic or organic acid, in solution such as in dimethylformamide, at 50.degree. to 100.degree. C. to form a 1-[(dimethylamino)methyl]-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiaz epine. A specific application of that process would be to react 8-chloro-1-hydrogen-6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine (now known by the generic name estazolam) with dimethylaminomethylene chloride salt to form 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzo diazepine (now known by the generic name, adinazolam). Estazolam and related compounds are described and claimed in Hester, Jr., U.S. Pat. No. 3,987,052, and in foreign equivalent patents of Takeda Chemical Company of Japan. Adinazolam is described and claimed with other compounds in Hester, Jr., U.S. Pat. No. 4,250,094. Additional 1-aminomethyl-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepine compounds, which can be made according to the improved process of this invention are described in the above Gall, U.S. Pat. No. 4,001,262, Hester, Jr., U.S. Pat. No. 3,734,922 and other patents and publications.
The process in the above Gall, U.S. Pat. No. 4,001,262 describes the need for chromatography procedures to separate and purify the desired 1-aminomethyl compound thereof (II) from the undesired but often coformed isomeric 4-aminomethyl- and 1,4-bis-aminomethyl-compounds as well as from by-product salts of the reaction. While column chromatography is convenient to use for purifying and separating chemical compounds on a laboratory scale, it is inconvenient for the purification of products in pilot plant or production plant scale procedures, where quantities of desired drug compounds are prepared on scales ranging from 5 to 5,000 kilograms per lot and larger. Moreover, silica gel, used for column chromatography, is costly, and such chromatography, if carried out at all, is time consuming and labor intensive.
Moreover, since the time of the invention described in the Gall, U.S. Pat. No. 4,001,262 chemical studies have continued by persons in the art to find practical methods for improving the yields of the desired 1-aminomethyl-product, e.g., adinazolam, over the whole course of this process including what goes on in the initial reaction mixture and in the subsequent work-up procedures. There is a need to improve the above referenced process for use in manufacturing 1-aminomethyl-compounds of the above Gall patent type, U.S. Pat. No. 4,001,262, which are of significant commercial and practical value as important and useful active drug compounds.
In studies of reactions of this process on related compounds attempts to minimize 4-aminomethyl- and 1,4-bis(aminomethyl)-group substitution in the ring system I, by inclusion of calcium hydride and 1,8-bis(dimethylamino)naphthalene have failed to minimize the formation of complicating side, by-product yield lowering 4-aminomethyl- and 1,4-bis(aminomethyl)-compounds.
The inventive advance in the art of carrying out the reaction and in identifying selective extractive conditions for separating the desired products (V), e.g., adinazolam, from their reaction mixture, solvents and by-products and the success of the resulting invention is reflected in the objects and description of the process improvements which follow.